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Alkaloids with a phenylhydrazone architecture are rarely found in nature. Four unusual phenylhydrazone alkaloids named talarohydrazones A–D (1–4) were isolated from the deep-sea cold seep derived fungus Talaromyces amestolkiaeHDN21-0307 using the one strain–many compounds (OSMAC) approach and MS/MS-based molecular networking (MN) combined with network annotation propagation (NAP) and the unsupervised substructure annotation method MS2LDA. Their structures were elucidated by spectroscopic data analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Talarohydrazone A (1) possessed an unusual skeleton combining 2,4-pyridinedione and phenylhydrazone. Talarohydrazone B (2) represents the first natural phenylhydrazone-bearing azadophilone. Bioactivity evaluation revealed that compound 1exhibited cytotoxic activity against NCI-H446 cells with an IC50value of 4.1 μM. In addition, compound 1displayed weak antibacterial activity toward Staphylococcus aureuswith an MIC value of 32 μg/mL.

Six new angucycline derivatives, named monacycliones G–K (1–5) and ent-gephyromycin A (6), as well as three known ones (7–9) were discovered from the marine sediment-derived actinomycete Streptomycessp. HDN15129 guided by Global Natural Products Social (GNPS) molecular networking. Structures including absolute configurations were elucidated by extensive NMR, MS, and ECD analyses. Among them, monacyclione G (1) possesses a unique scaffold featuring a xanthone core linked to the aminodeoxysugar ossamine, and monacycliones H–J (2–4) are rare examples of natural angucyclines with an S-methyl group. Monacycliones I and J (3and 4) showed cytotoxic activity against multiple human cancer cell lines, with IC50values ranging from 3.5 to 10 μM.

Ten new epipolythiodioxopiperazines (ETPs), namely, amphiepicoccins A–J (1–10), were isolated from the fish-gill-derived fungus Epicoccum nigrumHDN17-88. Their structures were deduced from extensive spectroscopic data and electronic circular dichroism (ECD) calculations. Amphiepicoccin A (1) which contains an aromatic indole motif is unprecedented among the epicoccin type of ETPs. Compounds 1, 3, and 6displayed anti-HSV-2 activities, with IC50values of 70, 64, and 29 μM, respectively (acyclovir as positive control with an IC50value of 31 μM), while 5and 6also revealed inhibitory activity against Bacillus subtiliswith minimum inhibitory concentration (MIC) values of 13 and 25 μM, respectively.

Nine previously undescribed prenylated p-terphenyls, prenylterphenyllins F–J (1, 2, 4–6) and prenylcandidusins D–G (3, 7–9), were isolated from an endophytic fungus, Aspergillus candidusLDJ-5. Their structures were determined from NMR and MS data. Differing from previously reported p-terphenyls, compound 3represents a rare 6,5,6,6-fused ring system. Compounds 4–6are antimicrobial, and compounds 1, 4, 6, and 9are cytotoxic.

Four new polyketides, penitalarins A–C (1–3) and nafuredin B (4), together with the known biogenetically related nafuredin A (5) were isolated from a mixed culture of a deep-sea-derived fungus Talaromyces aculeatusand a mangrove-derived fungus Penicillium variabile. Liquid chromatography/mass spectrometry analysis showed that none of compounds 1–5was produced by either of the two fungi when cultured alone under the same condition. The structures of 1–4, including absolute configurations, were deduced based on the interpretation of MS, NMR data, and time-dependent density functional theory calculations of specific electronic circular dichroism spectra. Compounds 1–3possess a 3,6-dioxabicyclo[3.1.0]hexane ring, and 4showed cytotoxicity with IC50values ranging from 1.2 to 9.8 μM against a panel of human cancer cell lines.

Four new alkyl aromatics, penixylarins A–D (1–4), along with the known biogenetically related 1,3-dihydroxy-5-(12-hydroxyheptadecyl)benzene (5) and 1,3-dihydroxy-5-(12-sulfoxyheptadecyl)benzene (6), were isolated from a mixed culture of the Antarctic deep-sea-derived fungus Penicillium crustosumPRB-2 and the mangrove-derived fungus Xylariasp. HDN13-249. UPLC-MS data and an analysis of structural features showed that compounds 1and 2were produced by collaboration of the two fungi, while compounds 3–6could be produced by Xylariasp. HDN13-249 alone, but in noticeably increased quantities by cocultivation. Compounds 2, 3, 5, and 6showed antibacterial activity against a panel of strains, and compound 3possessed potential antituberculosis effects (MIC = 6.25 μM against Mycobacterium phlei).

Two new polyketides modified with a rare methylsulfonyl group, 3-methoxy-6-methyl-5-(methylsulfonyl)benzene-1,2,4-triol (1) and neosartoryone A (2), along with a biogenetically related compound (3), were isolated from Neosartorya udagawaeHDN13-313 cultivated with the DNA methyltransferase inhibitor 5-azacytidine. The methylsulfonyl group of 1and 2was proven to be derived from DMSO, which was used as the solvent to dissolve 5-azacytidine. This is the first report of a fungus that can achieve a sulfonylation-like modification of natural products utilizing DMSO as a sulfur source. Compound 2showed lipid-lowering activity in vitrocomparable to simvastatin.

Four new tetramic acids, cladosins H–K (1–4), and a related known compound, cladodionen (5), were isolated from the culture of the Mariana Trench (depth 6562 m) sediment-derived fungus Cladosporium sphaerospermumL3P3 treated with the histone deacetylase inhibitor SAHA (suberanilohydroxamic acid). Interestingly, compounds 1–5existed as equilibrium E/Zmixtures and 1–4were the first cases of tetramic acids containing aniline moieties. Their structures including absolute configurations were elucidated through a combination of NMR, MS, and Mosher’s method, together with the consideration of biogenetic origins. Incubation experiments of exogenous aniline and N-phenyloctanamide revealed that the aniline moiety in cladosins H–K (1–4) is probably derived from the degradation of SAHA, indicating that the well-known histone deacetylase inhibitor SAHA could be metabolized by L3P3 and provide aniline as a precursor for biotransformation of chemically reactive polyketides. The cytotoxicity of 1–5was evaluated against the PC-3, MGC-803, SH-SY5Y, HCT-116, K562, and HL-60 cell lines, and compound 2showed promising cytotoxicity against the HL-60 cell line with an IC50value of 2.8 μM.

Fifteen meroterpenoids (1–15) with diverse ring systems including an unprecedented oxaspiro[5.5]nonane-fused cyclohexenone (1), hydrogenated benzofurans (2–5), hydrogenated chromans (6, 7), hydrogenated cyclopenta[b]chromans (8–11), and four monocyclic structures (12–15) were isolated from the sponge-associated fungus Alternariasp. JJY-32. The structures were elucidated by detailed spectroscopic analysis, including 2D NMR and electronic circular dichroism (ECD) calculations, and assisted by chemical derivatizations. On the basis of supplementation experiments with specific enzyme inhibitors and putative precursors, a shikimate–isoprenoid hybrid biosynthetic pathway is proposed. The NF-κB inhibitory activities of 1–15were tested, and all of them, except 6and 7(IC50> 100 μM), showed activities with IC50values ranging from 39 to 85 μM in RAW264.7 cells.

Sixteen new biisoflavones, bisoflavolins A–N (1–16), were discovered from cultures of the Takla Makan desert-derived strain Streptomycessp. HDN154127. The chemical structures, including axial chirality, were elucidated by NMR, MS, and ECD analyses. Antibacterial activity of dimerized compounds was tested against seven different bacteria. The dimerized compounds showed better activity (MIC from 0.8 to 50.0 μM) than the corresponding monomers (daidzein and genistein, MIC > 50.0 μM). The rare dimeric and chlorinated structures in 1–16were proved to be biotransformation products obtained from soy isoflavones and sodium chloride, which constituted the culture medium. This is the first report of an actinomycete that promotes both dimerization and chlorination utilizing natural isoflavones as skeletons sources.

Six new nonadride derivatives, named talarodrides A–F (1–6), were isolated from the Antarctic sponge-derived fungus Talaromycessp. HDN1820200. All structures including the absolute configurations were deduced by extensive spectroscopic analysis and computational ECD calculations. Compounds 1–4share a rare caged bicyclo[4.3.1]-deca-1,6-diene with a bridgehead olefin and maleic anhydride core skeleton, while compounds 5and 6possess the first case of a naturally occurring 5/7/6 methanocyclonona[c]furan skeleton. Talarodride A (1) and talarodride B (2) showed selective inhibitory effects against Proteus mirabilisand Vibrio parahemolyticuswith MICs of 3.13–12.5 μM.

Assisted by MS/MS-based molecular networking and X-ray diffraction analysis, five new p-terphenyl derivatives, namely, nocarterphenyls D–H (1–5), were obtained and characterized from the cultures of the marine sediment-derived actinomycete Nocardiopsissp. HDN154086. The skeleton of nocarterphenyl D (1) was defined to possess a rare 2,2′-bithiazole scaffold, naturally occurring for the first time, and nocarterphenyls E–H (2–5) are p-terphenylquinones with unusual thioether linked fatty acid methyl ester substitutions. Compound 1showed promising activity against multiple bacteria with MIC values ranging from 1.5 to 6.2 μM, and 2exhibited notable antibacterial activity against MRSA which surpassed the positive control ciprofloxacin.